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cachexia
cmbm exam V
52
Chemistry
Graduate
02/20/2010

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Term
know this -> what is cachexia?
Definition
a wasting syndrome that involves altered metabolism of proteins/carbs/lipids; resulting in anorexia, weight loss (unintentional >5% in 6 mos), loss of lean body and fat mass (disporportionate muscle wasting), decreased albumin (from altered protein metabolism), and increased C-reactive protein (marker of inflammation)
Term
know this -> what are the clinical manifestations of cachexia?
Definition
nonvoluntary weight loss, anorexia, early satiety (delayed stomach emptying), hypermetabolism (high resting energy expenditure), loss of lean body and total body mass (significant proteolysis and lack of protein synthesis particularly in skeletal muscle), loss of body fat (significant lipolysis), anemia (mediated by anemia inducing substance), weakness, and poor physical performance
Term
what are cachexia-related diseases? what is the link between these diseases and cachexia?
Definition
CA, RA, end-stage renal disease, CHF, HIV/AIDS, chronic obstructive pulmonary disease, and chronic liver disease (20-40% risk with each of these, pro-inflammatory cytokines are the link between these diseases and cachexia)
Term
what is the definition of cancer cachexia?
Definition
a wasting syndrome involving the loss of muscle and fat directly caused by an aberrant host response to the tumor presence
Term
what % of cancer pts have syptoms of cachexia? what % die from it?
Definition
50-80% have symptoms, 20% die
Term
which cancers cause the worst cachexia?
Definition
lung, pancreatic and gastrointestinal
Term
what is the general definition of starvation?
Definition
the body enters an energy conserving state, it tries to prevent lean body mass loss and weight loss
Term
what kind of metabolism is cachexia?
Definition
an energy wasting metabolism
Term
what happens to resting energy expenditure between starvation and cachexia?
Definition
in starvation, resting energy expenditure goes down, but in cachexia, it goes up (due to a constantly high level of epinephrine in the blood increasing the energy metabolism)
Term
why do people with cachexia have high blood glucose?
Definition
a constant level of cortisol is released that leads to insulin resistance
Term
what is the metabolic trend in terms of energy source in starvation?
Definition
at first, AAs are released from skeletal muscle, but this is shifted to ketone bodies as starvation progresses (lose more fat, less protein/muscle - gluconeogenesis is decreased)
Term
what is the metabolic trend in terms of energy source in cachexia?
Definition
tumors need a lot of glucose, which they convert to lactate, which is very inefficient. muscles are targeted for breakdown b/c they have glucogenic amino acids (ketone production is suppressed)
Term
do people in cachexia also lose fat as well as muscle?
Definition
yes; excess fat oxidation leads to depletion of fat mass w/elevated triglycerides and decreased lipoprotein lipase activity
Term
what is the primary source of weight loss in starvation?
Definition
primary weight loss is fat, with secondary loss of skeletal muscle and visceral protein mass
Term
what is the primary source of weight loss in cachexia??
Definition
there is equal loss of fat and lean body mass. skeletal muscle comprises the bulk of protein loss w/preservation of visceral protein mass
Term
is there a desire to eat in starvation and cachexia?
Definition
yes, w/starvation there is a increasing desire to eat, where with cachexia neuropeptide Y (responsible for food-seeking behavior) is suppressed, and hunger is decreased
Term
how does starvation respond to increased caloric intake?
Definition
weight loss is reversed
Term
how does cachexia respond to increased caloric intake?
Definition
there is an inability to gain or maintain weight despite adequate caloric intake; proteolysis and lipolysis not diminished with increase intake of substrates
Term
what does neuropeptide Y do?
Definition
when a person is hungry, neuropeptide Y increases in the hypothalamus thus increasing the person’s food seeking behavior
Term
what cytokines are most prominent in cancer related cachexia? where are they released from? what is their significance?
Definition
IL-1 alpha and beta, IL-6, TNF-alpha, and IFN gamma. these are released from white blood cells, skeletal muscle, and the tumor itself - these cytokines are the regulators and mediators of cachexia. they suppress neuropeptide Y, promote altered energy metabolism where anerobic processes are predominant, they promote cortisol and epinephrine release from the adrenal glands (insulin resistance/boost in energy metabolism), they directly stimulate proteolysis and lipolysis as well as promoting PIF/LMF in tumor cells
Term
are there other substances beyond cytokines that are released and play a part in cachexia?
Definition
yes, prostaglandin E-2 (PGE2), 15-hydroxyeicosatetraenoic acid (HETE), and reactive oxygen species (ROS) are also released.
Term
what special role do the ROSs released in cachexia play?
Definition
these ROS damage DNA and cells membranes, but also *activate enzymes.
Term
are there proteins that tumors secrete that promote cachexia?
Definition
yes, proteolysis inducing factor (PIF - mediates skeletal muscle breakdown through ubiquitin-proteasome pathway) and lipid mobilizing factor (LMF - inhibits lipoprotein lipase and stimulates hormone sensitive lipase) are released
Term
how are ROS, arachidonic acid and cachexia related?
Definition
in inflammatory processes, macrophages release ROS which activate PLA2 (phospholipase A2) which causes arachidonic acid from the phospholipid bilayer of cell membranes. arachidonic acid is then cleaved by COX 1+2 into series 2 prostaglandins, series 4 leukotrienes and *PGE2
Term
what is PGE2's significant role in cachexia?
Definition
PGE2 leads to the activation of transcription and translation of cytokines
Term
what else does arachidonic acid get cleaved into besides series 2 prostaglandins and series 4 leukotrienes and PGE?
Definition
HPETE which is the result of lipoxygenase cleavage. HPETE induces tumor cells to produce PIF and LMF
Term
if which 2 enzymes were arrested, would cachexia stop?
Definition
cyclooxygenase and lipooxygenase
Term
what is the key to treating cachexia via nutritional care?
Definition
cytokine antagonism, with the cornerstone being medications/nutriceuticals to counteract the pathophysiology
Term
what do progestagens megesterol and medroxyprogesterone acetate do?
Definition
these inhibit cytokine production and counteract neuropeptide Y down regulation
Term
what does thalidomide do?
Definition
profoundly blocks the production of cytokines
Term
what does testosterone do?
Definition
inhibits the effects of cytokines in proteolysis and promtes protein synthesis in muscle
Term
what do NSAIDs do?
Definition
inhibit COX, therefore inhibiting PGE2 and cytokine production (ibuprofen, indomethacin, celecoxib)
Term
what does eicosapentaenoic acid (EPA) do?
Definition
this nutriceutical has proven to be the most effective in managing cytokines of cachexia. it competes with arachidonic acid for COX/LOX; decreasing series 2 and 4 eiconasoids and increasing series 3 and 5 eiconasoids
Term
what are nutriceuticals?
Definition
foods or food-derived substances that can have pharmalogical effects
Term
what are dronabinol and reglan?
Definition
these both increase neuropeptide Y. dronabinol is a chemical relative of marijuana.
Term
where does arachidonic acid come from?
Definition
linoleic acid from food
Term
where does EPA (eicosapentanoic acid) come from?
Definition
linolenic acid (from which DHA - docosahexaenoic acid, another omega fatty acid also comes)
Term
what is the difference in eicosaniod production between consumption of predominately omega 6 and 3?
Definition
omega 6:linoleic acid -> arachiconic acid -> COX -> series 2 prostaglandins and series 4 leucotrienes (more inflammatory cytokines). omega 3: linolenic acid -> competitive for COX -> EPA ->DHA -> series 3 prostaglandins, series 5 leucotrienes (less inflammtory cytokines)
Term
what does EPA inhibit?
Definition
release of arachidonic by phospholipase A from plasma membranes, competes with COX/LOX in a matter that inhibits prostaglandin 2 and leuctriene 4 production, and NFkappaB (nuclear transcription factor) for the production of cytokines
Term
what is an effective dose of EPA/day?
Definition
2-3 grams
Term
can EPA depress muscle proteolysis?
Definition
yes
Term
what do polyphenols do? what are some examples?
Definition
polyphenols such as catechin (green tea) and resveratol (grapes) inhibit PIF, (and therefore proteolysis), COX and cytokine production are inhibited
Term
how can antioxidants like vitamins A, C, E, alpha-lipoic acid help with cachexia?
Definition
these quench ROSs (reduced stimulus for phospholipase A to release arachionic acid)
Term
what will leucine (a branched chain AA) do in 3g per day quantities?
Definition
enhance protein synthesis
Term
how can HMB (beta hydroxy beta methylbutyrate - metabolite of leucine) + arginine + glutamine help reverse cachexia?
Definition
HMB+arginine+glutamine together counteract PIF. individually, arg and glut (14g/day) enhance protein synthesis and HMB (3g/day) minimizes proteolysis
Term
once the cytokine (inflammatory) problem has been addressed in cachexia, what is the next step?
Definition
hypercaloric feeding, with enteral emphasis. there are commercial formulas that have included in them many of the necessary nutriceuticals already. extra (catch-up) feedings may be necessary between chemo bouts (this may include paraenteral/enteral feeding depending on appetite).
Term
why is using cold liquid food useful in cachexia?
Definition
it leaves the stomach faster than hot/solid food
Term
what is the key to treating pts with anorexia (after inflammation of cachexia has subsided)?
Definition
let them eat whatever they want (might have food jags)
Term
how can nutrient density be increased in food?
Definition
adding (flax) oil, milk powder, egg whites
Term
after addressing inflammation and nutrient deficit, what is the next step in recovery from cachexia?
Definition
resistance training, promotion of physical activity to stimulate muscles toward protein anabolism. 3 days/wk, 12 large muscle groups with 3 sets of weight that the pt can't life more than x
Term
what needs to be treated before aggressive nutrition therapy can work?
Definition
the chronic inflammatory state
Term
what can be done early to prevent substantial weight loss before tx?
Definition
assessment of cachexia
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